IJBCP International Journal of Basic & Clinical Pharmacology ...

Print ISSN: 2319-2003 | Online ISSN: 2279-0780

IJBCP

International Journal of Basic & Clinical Pharmacology

doi: 10.5455/2319-2003.ijbcp20131002

Research Article

Chronic alcohol use affects therapeutic steady state plasma drug concentrations of stavudine, lamivudine and nevirapine in HIV-infected patients during 9 months follow up period: WHO AUDIT tool application Godfrey S. Bbosa1*, David B. Kyegombe2, William W. Anokbonggo1, Muhammad Ntale3, David Musoke4, John Odda1, Aloysius Lubega1, Jasper Ogwal-Okeng1

1

Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, Uganda 2 Department of Pharmacology and Toxicology, Kampala International University School of Health Sciences, Busyenyi, Uganda 3 Department of Chemistry, Makerere University College of Natural Sciences, Uganda 4 Department of Pharmacology and Therapeutics, Gulu University Medical School, Uganda Received: 10 July 2013 Accepted: 21 July 2013 *Correspondence to: Dr. Godfrey S. Bbosa, Email: [email protected]/godfossa@gmail. com © 2013 Bbosa GS et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT Chronic alcohol consumption is a common problem among the HIVinfected patients on HAART. The study determined the effect of chronic alcohol use on steady state plasma drug concentrations of stavudine (d4T), lamivudine (3TC) and nevirapine (NVP) in HIV-infected patients during the 9 months follow up period. It also determined whether there were some patients with undetectable plasma drug concentrations in their plasma during the follow up. A case control using repeated measures design with serial measurements model, where plasma drug concentrations were measured at 3 month intervals was used. Chronic alcohol-use using WHO AUDIT tool was used to screen patients. A total of 41 patients (21 alcohol group and 20 control group) were followed up for 9 months with blood sampling done at 3 month intervals. The Shimadzu Class-VPTM HPLC Chromatography data system version 6.1 equipment with UV detector was used to measure the plasma drug concentrations. Data was analyzed using SAS 2003 version 9.1 statistical package with repeated measures fixed the model and means were compared using the student t-test. The mean steady state plasma concentration of both d4T and 3TC in chronic alcohol use group were lower than in the control group all throughout the 9 months period of follow-up. The mean steady state plasma drug concentrations of NVP were higher in the alcohol group at 0 and 3 months and lower in the 6 and 9 months as compared to the control group. The mean total plasma NVP concentration was higher in the chronic alcohol group as compared to the control group and the difference was statistically significant (p≤0.05). However some patients had undetectable plasma drug concentrations despite of having ≥ 95 % adherence rate. Chronic alcohol use by the HIV-infected patients lowers the steady state plasma drug concentrations of d4T, 3TC and NVP in patients. Keywords: Chronic alcohol use, Therapeutic steady state plasma drug concentrations, HIV, d4T, 3TC, NVP

INTRODUCTION Chronic alcohol use is a global problem. The World Health Organization (WHO) estimates that about 2 billion people worldwide consume alcoholic beverages and 76.3 million people experiences diagnosable alcohol use disorders.1-3 Alcohol mainly ethanol or ethyl alcohol

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is found in many alcoholic beverages such as wine, spirits, liquors, beers and traditional brew and it is by far the most abused drug for centuries in the different countries world over.4 In Uganda, alcohol consumption is a serious problem and is a widely accepted social drink in the cultural and ceremonial activities.5-7 Among the chronic alcohol consumers in Uganda are the HIV-

International Journal of Basic & Clinical Pharmacology | September-October 2013 | Vol 2 | Issue 5

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Bbosa GS et al. Int J Basic Clin Pharmacol. 2013 Oct;2(5):507-516

infected patients on the highly active antiretroviral therapeutic (HAART) drugs like stavudine (d4T), lamivudine (3TC) and nevirapine (NVP) drug regimen. However the pharmacokinetics (absorption, distribution, metabolism and excretion – ADME) of these drugs can be affected by the use of chronic ethanol and its metabolites. Alcohol is metabolized by both the hepatic and extrahepatic enzyme systems.8 The most common extrahepatic metabolizing enzyme being alcohol dehydrogenase enzyme isoforms, aldehyde dehydrogenase enzyme isoforms and catalase found mainly in the gut wall in males and in the liver in females.8-10 Some of the hepatic microsomal ethanol oxidizing systems (MEOS) include cytochrome 2E1 (CYP2E1), CYP1A2 and CYP3A4 with CYP2E1 the main alcohol metaboliser in the liver. The activity of CYP2E1 may be induced or inhibited in some individuals especially in chronic alcohol consumption and it varies among people.8,9,11,12 There is a sex difference in alcohol metabolism where in males it is mainly metabolized in the gastrointestinal tract (GIT) while in females, metabolism occurs in the liver.8,9,11,13 The products of the alcohol metabolism affect the body’s physiological processes especially the liver and the kidney that responsible for the elimination of drugs from the body and hence affecting the pharmacokinetics of d4T, 3TC and NVP drugs used by the patients.14,15 This may significantly affect the therapeutic steady state plasma drug concentrations (therapeutic window) available to suppress the HIV virus. Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) and administered as 30 mg every 12 hours. Its binding to serum proteins has been reported to be negligible over the concentration range of 0.01 to 11.4 μg/mL and distributes equally between red blood cells and plasma. The therapeutic steady state plasma concentration of d4T in healthy volunteers has been reported be 0.09-0.68 μg/ml. The mean terminal elimination half-life ranges 0.8-1.5 hours in adults following single oral dose, and is independent of dose. About 40-50% of stavudine dose is reported to be excreted unchanged in urine and the remaining 60% is presumably eliminated by endogenous pathways.16-18,47 Lamivudine is also an NRTI, administered as 150 mg twice daily. The steady state plasma concentration of lamivudine in healthy volunteers is reported to be 0.2 to 1.42 to µg/mL. About 70% to 80% is excreted unchanged in urine by the active cationic secretion via glomerular filtration and tubular secretion with minor metabolism. It has a mean terminal half-life of elimination of 5 to 7 hours with the intracellular half-life of the lamivudine 5’triphosphate, the active metabolite being 10.5 to 15.5 hours and 17 to 19 hours in HIV-1 and hepatitis B virus (HBV) infection and peripheral blood lymphocytes cell lines respectively.16-19,48 The nevirapine (NVP) is a nonnucleoside HIV-1 reverse transcriptase inhibitor (NNRTI) with a potent and selective inhibitor of the replication of a wide variety of HIV-1 strains in several cellular assays.16,17,19 Nevirapine is administered at a dose

of 400mg/day in adults and has a therapeutic steady state plasma concentration of 5.3 to 11.7 µg/mL with a halflife of 25-30 hours following multiple dosing.More than 80% of a nevirapine dose is biotransformed via CYP450 oxidation to hydroxylated metabolites that are mainly excreted in urine as glucuronides. Only a small fraction of administered dose (0.05) in mean d4T plasma drug concentrations for all the drugs at different time interval in both groups. However, similar trend was observed for the 3TC. The NVP mean plasma drug concentrations was higher in the chronic alcohol-use

group as compared to the control group and there was significant difference (p=0.049) between the 2 groups. The results show some patients reported to have an adherence rate of above 95% were observed to have no detectable drug concentrations in their plasma (Table 6). For the d4T, 14.3% of the patients had no detectable plasma drug concentrations in their plasma in the 0 and 3 month period of follow up. In the 6 month, it was 15.8% and 11.1% in the 9 month of the follow up in the control group. In the chronic alcohol-use group, it was 5% in both the 0 and 3 month and 15% in the 6 month and 22.2% in the 9 month. For the 3TC, all the patients were observed to have detectable plasma drug concentrations in their blood in both the chronic alcohol-use and control group. For the NVP, all the patients in the chronic alcohol-use group had detectable plasma drug concentrations in their blood circulation while in the control group, 4.8% had no detectable plasma drug concentrations in the 0 and 3 month follow up. In the 6 month, all the patients had detectable plasma drug concentrations in their plasma while in the 9 month of follow up, 5.6% had no detectable drug plasma concentrations in the control group.

Table 4: Effect of chronic alcohol consumption on the mean steady state d4T, 3TC and NVP plasma drug concentrations in alcohol-use self reporting during the 9 month follow-up period. Time of follow-up (months) Mean plasma drug levels d4T ±SE (µg/mL)

0

3

6

9

Control

0.89±1.09

0.91±1.09

2.68±5.2

1.13±0.85

Alcohol

0.74±0.31

0.76±0.31

0.91±0.84

0.88±1.2

0.40

0.42

0.16

0.52

Control

3.62±2.75

3.7±2.82

4.74±2.06

4.36±3.3

Alcohol

3.48±0.98

3.58±0.9

3.31±1.09

4.18±3.34

0.68

0.67

0.07

0.85

Control

5.7±2.35

5.92±2.4

6.6±3.7

6.11±7.08

Alcohol

6.46±2.93

6.82±2.9

5.76±1.87

5.96±2.32

0.58

0.57

0.61

0.91

0.09-0.68

p-value 3TC ±SE (µg/mL)

0.2-1.42

p-value NVP ±SE (µg/mL) p-value

Therapeutic window

5.3-11.7

SE: standard error; d4T: stavudine; 3TC: lamivudine; NVP: nevirapine


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DISCUSSION Plasma drug levels (µg/mL)

8.00 7.00 d4T-c

6.00

d4T-a

5.00

3TC-c

4.00

3TC-a

3.00

NVp-c

2.00

NVP-a

1.00 0.00 0.0

3.0

6.0

9.0

Time (Months)

Figure 2: Variation of the mean d4T, 3TC and NVP steady state plasma drug concentrations with time for both chronic alcohol-use and control groups using alcohol-use self reported method. d4T-c: d4T in control group; d4T-a: d4T in chronic alcohol; 3TC-c: 3TC in control; 3TC-a: 3TC in chronic alcohol; NVP-c: NVP in control; NVP-a: NVP in chronic alcohol

Table 5: Comparison of mean d4T, 3TC and NVP plasma drug concentrations for alcohol-use selfreporting method. Mean drug levels d4T ±SE (µg/mL) 3TC ±SE (µg/mL) NVP ±SE (µg/mL)

Control group

Chronic alcohol consumption

p value

1.17±0.27

0.92±0.25

0.525

4.24±0.84

4.3±0.79

0.959

4.5±0.55

5.96±0.51

0.049

Table 6: Patients with undetectable d4T, 3TC and NVP plasma drug concentrations in their blood.

ARV drug

% of HIV-infected patients with no detectable plasma drug levels during the time of follow-up (months) 0

3

6

9

14.3 (n=3) 5.0 (n=1)

10.0 (n=2) 10.0 (n=2)

15.8 (n=3) 15.0 (n=3)

11.1 (n=2) 22.2 (n=4)

Control

0.0

0.0

0.0

0.0

Alcohol

0.0

0.0

0.0

0.0

Control

4.8 (n=1)

0.0

0.0

5.6 (n=1)

Alcohol

0.0

5.0 (n=1)

0.0

0.0

Control d4T Alcohol 3TC

NVP

The results in the table 4 show that the steady state plasma drug concentrations of d4T and 3TC were higher than the therapeutic steady state plasma drug concentration reference ranges of 0.09 – 0.68 µg/ml and 0.2 – 1.42 µg/ml respectively in both the chronic alcohol use and control group throughout the 9 month follow up period. The high plasma drug concentration of d4T and 3TC could be due to the drug formulation problem where pharmaceutical companies may have more active drug ingredients being incorporated in the drug during the compounding above the recommended pharmacopoeia standards.40,41 This leads to the drug toxicity possibly observed in the HIV-infected patients on prolonged treatment thus requiring instituting of the therapeutic drug monitoring and consideration of the personalized medicine during the treatment of the patients. Also since the patients are on prolonged treatment and together with the high steady state plasma drug concentrations of d4T and 3TC above the reference ranges, these causes the liver and kidney toxicity and yet these organs are responsible for the elimination of the these drugs from the body and hence causing their accumulation due to the delay in their elimination thus leading to the observed effect in the study.42,43 However the steady state plasma drug concentrations of d4T and 3TC in the chronic alcohol use group were lower than the control group and this could be due to the diuretic effect of ethanol and its metabolites since these drugs undergo 80% excretion as free drug in unchanged form of which ethanol facilitates this process of elimination leading to the observed effects.29-31,44 Also the activation of the epigenetic mechanisms by alcohol may lead to gene expression of the of the drug transporters that facilitate the elimination of the drugs in urine from the body thus requiring consideration of individualized medicine.29-31,44 The NVP steady state plasma drug concentration was variable during the 9 months follow up period. It was higher in chronic alcohol group at 0 and 3 month of follow up and lowers in the 6 and 9 months. It was possible that at 0 and 3 month, NVP suppressed the CYP450 metabolizing enzyme and then at the 6 and 9 month, the ethanol metabolites activated the metabolizing system thus causing the variation in mean steady state plasma drug concentrations of NVP in the patients. NVP is mainly eliminated from the body by CYP450 enzyme metabolism especially CYP3A and CYP2B6 pathways and these isoenzymes can also be autoinduced by ethanol thus facilitating the clearance of NVP from the plasma. The observed high plasma drug levels of d4T and 3TC in some patients could also be due to the suppressed epigenetic mechanisms by the drugs themselves (nucleoside and non-nucleoside analogues that are DNA methyltransferases (DNMTs) inhibitors) and as well as exposure to other environmental factors like the alcohol, herbs and dietary substances by the individual patients that may suppress gene expression that encodes for the CYP450 drug metabolizing enzymes especially for NVP


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that undergo CYP450 metabolism thus leading to the failure of drug transport from blood circulation to tissues.24-27,44,45 Also SNPs may be triggered by ethanol and its metabolites and other environmental exposures by the patients such as herbs and foods may have contributed to the observed high d4T and 3TC plasma drug levels by suppressing the CYP450 and drug transport system thus delaying the elimination of the drugs from the body in some patients.29-31,44 These result in accumulation of the d4T and 3TC drugs in blood circulation observed in the study and this could be the reason to why most of these patients experience toxicity after prolonged period off treatment. However, the mean total steady state plasma drug concentrations of d4T, 3TC and NVP (Table 5) in both the chronic alcohol use group and the control group were varying and this could be due to the contribution of the observed undetectable plasma drug concentrations in some patients that could have affected the mean total steady state plasma drug concentrations in the patients. Undetectable plasma drug concentration in the HIVinfected patients In the control group, the undetectable d4T and NVP plasma drug concentration could be due to the poor quality (fake and substandard) drugs which the patients may have been exposed to during their treatment in which there were no active ingredients in the drug during the drug formulation by the pharmaceutical companies.40,41 It may also be due to the effect of adherence in which the methods used (pill count at scheduled visits and self reporting) are not sensitive enough to detect any patients who were not adhering to the treatment leading to missed doses that affects the steady state plasma drug concentrations in the patients as observed in the study. In the chronic alcohol use group, other than the poor quality of the drugs and poor adherence, ethanol and its metabolites may contribute to a significant effect on the rapid elimination especially excretion of d4T and 3TC since 80% of these drugs are excreted as free drugs in urine. The observed undetectable d4T and NVP plasma drug levels in some patients in both the alcohol group and the control group may be due to the activation of the epigenetic mechanisms by some environmental factors such as dietary and herbal substances, ethanol and its metabolites that may increase the over expression of the genes that encode the CYP450 metabolizing enzymes and the drug transporter proteins that cause rapid elimination of drugs from the body.27,29-31 In alcohol group, ROS may have played a significant role in gene expression. In the control group, the undetectable plasma levels may also be due to SNPs as a result of mutations of the genetic code leading to over expression of CYP450 enzyme systems and transport proteins leading to rapid elimination of the d4T and NVP drugs from the body observed in the group.29-31 Also alcohol has a diuretic effect that inhibits the secretion of antidiuretic hormone (ADH) from both the supraoptic and paraventricular nuclei of the

hypothalamus33,34 and this increase the excretion of the d4T and NVP free drugs in urine in unchanged form thus lowering the drugs half-lives.10,32,36,46 The diuretic effect of alcohol32,33 leads to the continued excretion of the d4T drugs as a free drug in urine that may lead to the undetectable levels as observed.10,43 These processes can lead to the sub-therapeutic plasma drug concentrations that cannot suppress HIV virus thus promoting the emergence of resistance, increase in the viral load and therapeutic failures. However, on the other hand, poor quality drugs, especially the drugs have no active ingredient could lead to undetectable plasma drug concentrations in circulation as observed in the patients. And if there too much active ingredients during formulation, toxicity may be a problem since patients will be operating in toxic drug concentrations ranges as observed in the study. CONCLUSION Chronic alcohol use, HIV disease and d4T, 3TC and NVP interact and affect the therapeutic steady state plasma drug concentrations in the HIV-infected patients. Ethanol and the accumulation of its metabolites in the body can damage the kidney and the liver that eliminate drugs from the body thus affecting the therapeutic steady state plasma drug concentration leading to the observed high levels of the drugs above the reference ranges. The undetectable d4T and NVP plasma drug concentrations in some patients may be attributable to poor adherence and poor quality drugs and these affect the therapeutic steady state plasma drugs levels that in turn affect the therapeutic outcome and recovery of the patients. ACKNOWLEDGEMENTS We would like to thank the following individuals who greatly contributed to the success of this work and without them, it would have been impossible to do this study. We want to thank Mr. Gordon Ewa in the Dept of Pharmacology and Therapeutics, Makerere University College of Health Sciences and Mr. Apollo Mugisha from the Clinical Chemistry Laboratory in National Referral Hospital Mulago Complex for their technical assistance in analyzing the samples. We want to thank Sr. Justine Birungi, Sr. Plaxeda, Sr. Namugosa, Sr. Jesca and Dr. Kayima from the St. Raphael of St Francis hospital, Nsambya, Private clinic who assisted us a lot in the recruitment of the subjects and the collection of blood samples from the patients. We want to thank the Director of St. Raphael of St Francis hospital, Nsambya and the Dr. Pius Okong, the chairman of IRB of the hospital for allowing us to conduct this study in the hospital. We want to thank Dr. Norah Mwebaza and Mr. Dan Kibuule of the Dept of Pharmacology and Therapeutics, Makerere University College of Health Sciences for their scientic support in the study. Funding: None Conflict of interest: None declared


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Ethics approval: Approved by the local ethical committee [Faculty of Medicine Higher degrees, Research and Ethics committee of Makerere University Institution Review Board (IRB) (IRB#-2007-060), IRB of St. Raphael of St Francis hospital, Nsambya (no. IRB 03: 01/03/2008) where the study participants were recruited from and the Uganda National Council for Science and Technology (UNCST)(no. HS 387)]

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doi:10.5455/2319-2003.ijbcp20131002 Cite this article as: Bbosa GS, Kyegombe DB, Anokbonggo WW, Ntale M, Musoke D, Odda J, Lubega A, Ogwal-Okeng J. Chronic alcohol use affects therapeutic steady state plasma drug concentrations of stavudine, lamivudine and nevirapine in HIV-infected patients during 9 months follow up period: WHO AUDIT tool application. Int J Basic Clin Pharmacol 2013;2:507-16.


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